ACRYLONITRILE
Explanation
This compound has not been previously reviewed by the Joint
FAO/WHO Expert Committee on Food Additives.
Acrylonitrile (synonums: 2-propenenitrile, cyanoethylene, vinyl
cyanide) is a clear, colourless and highly flammable liquid that has
an unpleasant and irritating odour. It has the following chemical
formula:
H
C = C - C = N
H
H
The major use of acrylonitrile is a monomer in synthetic rubber
and plastics that may be used for food containers. The compounds is
also used in many countries as a fumigant for grain and as a
fluocculant in waste and water treatment plants.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
Single oral doses of 0.1 or 10 mg/kg of 14C-acrylonitrile given
to male albino rats were 95% absorbed while 5% was excreted in the
feces. Depending on the dose, 34.2% or 66.7% of the radiolabeled dose,
respectively, was excreted in the urine over a period of 72 hours.
Total recovery of the administered radioactivity was between 82 and
104% (Young et al., 1977).
The study of body burden (% of dose not excreted at the end of
the different time intervals) and of plasma concentration after oral
or intravenous administration of 14C-acrylonitrile, revealed a
biphasic disappearance of the radioactivity. This indicates a
pharmacokinetic two-compartment model for elimination. The half-life
values of alpha- and beta-phases, calculated by linear regression
analysis of plasma concentration curves, ranged from 3.5 to 5.8 hours
and 55 to 70 hours, respectively (Young et al., 1977). Seventeen
percent of an intravenous dose of 1 mg of acrylonitrile per kg body
weight was excreted in the bile but most of this radioactivity was
reabsorbed through the enterohepatic circulation (Young et al., 1977).
Freshour & Melcher (1983) observed a biphasic elimination after
oral administration of 30 mg of acrylonitrile per kg body weight to
rats (half-life of terminal phase 85-120 minutes) but a first-order
elimination pattern was found after intravenous administration.
Tissue distribution of radioactivity after single oral or
intravenous dosing of rats with 14C-acrylonitrile demonstrated high
levels in stomach, skin and erythrocytes regardless of route of
administration. The retention of radioactivity in the stomach wall
after intravenous administration indicates that the high concentration
of acrylonitrile in this site after oral dosing was not entirely
due to poor absorption (Young et al., 1977). The accumulation of
radioactivity in blood was mainly due to covalent binding of
acrylonitrile to macromolecules and lipids in the erythrocytes (Ahmed
& Patel, 1979).
Whole-body autoradiography after oral or intravenous
administration of 14C-acrylonitrile to rats or monkeys showed
similar distribution patterns. High levels of activity were present
in the blood and excretory pathways (bile, intestinal contents and
urine) with liver, kidney, lung and adrenal cortex accumulating
appreciable label. Stomach and hair follicles showed constant uptake
of label. Radioactivity was still present in rats, seven days after
administration. In fetuses, exposed in utero, only the eye lens
accumulated label higher than that observed in the maternal blood.
Monkeys displayed a more pronounced activity in the liver than rats
(Sandberg & Slanina, 1980).
Biotransformation
Two metabolites were identified in urine of rats exposed to
30 mg/kg of acrylonitrile by gastric intubation as thiocyanate and
N-acetyl-S (2-cyanoethyl)cysteine. A third was tentatively identified
as 4-acetyl-3-carboxy-5-cyanotetrahydro-1,4-2H-thiazine (Langvardt et
al., 1980). Acrylonitrile was not detected in the urine of these rats.
However, Houthuijs et al. (1982) have reported the excretion of
unchanged acrylonitrile in factory workers and proposed monitoring
urinary acrylonitrile as a measure of exposure.
Cyanoethanol and cyanoacetic acid were detected by gas
chromatography in the urines of rats injected i.p. with acrylonitrile
(Lambotte-Vandepaer et al., 1981).
In bile of rats exposed to acrylonitrile orally, 4 metabolites
were isolated. The two biliary metabolites were glutathione conjugates
of acrylonitrile (Ghanayem & Ahmed, 1982).
Using 14C-label on different parts of the molecule, Kopecky et
al. (1980) showed two metabolic pathways of acrylonitrile metabolism,
when administered to rats. The minor pathway, through glycidonitrile
and glycolaldehyde cyanohydrin, produced cyanide and subsequently
thiocyanate. The major metabolites were derived from glutathione
conjugation.
These pathways were confirmed in vitro with rat liver
microsomes. The cyanide formation being dependent on a cytochrome
P-450-dependent mixed function oxidase system (Abreu & Ahmed, 1980).
Duverger-van Bogaert, et al. (1981) isolated four metabolites:
cyanoacetic acid, cyanoethanol, acetic acid and glycolaldehyde from
rat liver homogenates after incubation with acrylonitrile.
Isolated rat hepatocytes were incubated with acrylonitrile. The
major glutathione-adduct formed was identified as S-(2-cyanoethyl)
glutathione. S-(2-cyanoethyl)-cysteine was the major adduct found in
radiolabeled protein. 2-cyanoethylene oxide accumulated in the cell
suspension. Cyanide appeared to be completely converted to thiocyanate
(Geiger et al., 1983).
Effects on enzymes and other biochemical parameters
Oral or i.p. administration of 40 or 100 mg/kg body weight of
acrylonitrile to mice caused inhibition of cytochrome oxidase in liver
and brain. At the highest dose, the enzyme inhibition persisted until
death. On the basis of identifiation of cyanide in these organs,
the authors postulated that this metabolite is responsible for the
observed effect (Nerudova et al., 1981).
Male rats were exposed intraperitoneally to 33 mg/kg body weight
of acrylonitrile for 3 days. Treatment resulted in a 20% decrease
in liver microsomal cytochrome P-450 activity. This decrease was
confirmed by a reduction in benzo(a)pyrene metabolism by liver
microsomes. Corticosterone and prolactin levels in the serum of these
animals were markedly reduced whereas FSH-levels doubled (Nilsen et
al., 1980).
Four hours after i.p. injection of acrylonitrile (30 mg/kg)
in hamsters glutathione levels in liver and brain were reduced.
Twenty-four hours after injection liver and kidney weights were
increased as were brain and kidney GSH-levels. Brain succinate
dehydrogenase and cytochrome oxidase levels were decreased as were
liver and kidney ethoxycoumarin deethylase and liver cytochrome P-450
(Zitting et al., 1981).
Although a one-time i.v. injection of acrylonitrile in rats
depleted liver, adrenal gland and brain of glutathione (GSH), a 21-day
exposure in drinking water at concentrations of 0, 20, 100 and 500 ppm
caused increased GSH levels in the liver (Szabo et al., 1977).
Vainio and Makinen (1977) demonstrated species specificity in the
GSH-depletion in liver comparing rats, hamsters and mice. The mouse
was most sensitive to one-time oral or intraperitoneal administration
and the rat the most resistant.
Irreversible covalent binding of acrylonitrile to rat liver
microsomal proteins in vitro was reported by Duverger-van Bogaert
(1982a). This observation was confirmed in vivo after i.p. injection
of acrylonitrile to rats (Peter & Bolt, 1981). Incubation of rat
liver microsomes with acrylonitrile also resulted in irreversible
binding to DNA, RNA or polynucleotides (Peter et al., 1983a).
TOXICOLOGICAL STUDIES
Special study on reproduction
Rat
A three-generation reproduction study was performed on
20 rats/dose consuming 0, 100 or 500 ppm of acrylonitrile in the
drinking water for 100 days before the first mating and throughout the
experiment, including during lactation. Two litters were produced in
each generation and the offspring of the second litter were used to
produce the next generation. In the first generation parental toxicity
signs were apparent at the 500 ppm level in the form of decreased
food-water consumption and body weights. In both litters of the first
generation, a greater number of pups died in the 500 ppm group. These
deaths may have been a result of acrylonitrile's toxicity to the dams,
since pups fostered by untreated dams had normal survival. The only
adverse effect observed in pups that survived treatment was a decrease
in body weight in the 500 ppm group in all litters. There was a
suggestion of tumorigenic activity in the females of the F1b
generation that were sacrificed after weaning of their second litter.
An increase was observed in astrocytomas in the brain (4 tumors out of
17 necropsied) in the 500 ppm group and Zymbal gland tumors (2 out of
19 and 4 out of 17 in the 100 and 500 ppm groups, respectively) while
no tumors were reported in the controls. No other histopathological
adverse findings were described (Beliles et al., 1980).
Special study on species specificity of fetotoxicity
Mouse
One single i.p. injection of 32 mg/kg body weight of
acrylonitrile in groups of 11-13 pregnant mice of the inbred AB
Jena-Halle strain on day 5, 7 or 9 of gestation caused an increase in
post-implantation loss of fetuses. No significant embryotoxic effect
was observed in DBA or C57B1 mice even after repeated applications
from day 1-14 or day 7-14 of gestation (Scheufler, 1980).
Special studies on teratogenicity
Hamster
Groups of 5 or 6 (12 for control) pregnant hamsters were treated
intraperitoneally with a single dose of physiological saline or 4.8,
10.1, 24.9, 65.3 or 80.1 mg/kg body weight of acrylonitrile on day 8
of gestation. Additional groups were pre- and post-treated with the
known cyanide antagonist sodium thiosulfate to investigate the role of
cyanide involvement in the teratogenic effects observed. The hamsters
were sacrificed on day 14 of gestation and fetuses were recovered by
caesarian section. Implantation and resorption sites were recorded,
and fetuses were examined under a dissecting microscope for skeletal
malformations. After fixation in Bouin's solution, the fetuses were
re-examined to confirm the observed abnormalities.
Maternal toxicity was observed at 80.1 mg/kg of acrylonitrile in
the form of respiratory distress, salivation and convulsions. At this
dose level, the number of resorptions was increased and 7 out of 51
live fetuses had an encephalocele (0/135 in controls). Treatment with
1.275 g/kg of sodium thiosulfate intraperitoneally, protected dams and
fetuses of toxic effects of acrylonitrile at this dose. However, at
higher dose levels of acrylonitrile (100 mg/kg) with sodium
thiosulfate, teratogenic effects were observed in the absence of
maternal toxicity. At 120 mg/kg of acrylonitrile, this dose of sodium
thiosulfate failed to protect the dams from maternal toxicity
(Willhite et al., 1981a).
The same authors studied the changes caused by 80.1 mg/kg of
acrylonitrile administered intraperitoneally to pregnant hamsters on
day 8 of gestation. Early embryos (10 hours after acrylonitrile
administration) and term fetuses (sacrificed on day 14 of gestation)
were studied histopathologically after hematoxylin-eosin staining.
Signs of acute mesodermal damage were noted 10 hours after dosage
including reduced cell number, shrinkage of cytoplasm, and enlarged
extracellular spaces. The affected embryos were smaller and were
delayed in their development. The treated embryos showed a shortening
of the neural folds and failure of the neural tube to close. The
14-day old fetuses showed cranioschisis occulta with encephalocele,
and axial lordotic malformations (Willhite et al., 1981b).
Rat
Between 29 and 39 pregnant rats were given 10, 25 or 65 mg/kg
body weight of acrylonitrile in water by gastric intubation on days
6-15 of gestation. A group of 43 control animals received an equal
volume of water (2 mg/kg body weight) by gavage. On day 21 of
gestation, the dams were sacrificed and examined for implantation
sites, resorptions and fetal abnormalities. Additional rats (30/group)
were exposed to 0, 40 or 80 ppm of acrylonitrile by inhalation for
6 hr/day during the same period. As determined by acrylonitrile blood
levels, the 80 ppm inhalation dose was equivalent to a 23 mg/kg oral
dose. The dams receiving 65 mg/kg body weight of acrylonitrile showed
signs of maternal toxicity in the form of hyperexcitability, excessive
salivation, thickening of the non-glandular portion of the stomach,
decreased weight gain, food consumption and increased water
consumption as well as increased absolute and relative liver weights.
In the 65 mg/kg gavage group, 4 pregnancies did not develop to term
but all fetuses were resorbed. However, in the remaining successful
pregnancies there was no indication of early fetal death (litter sizes
and resorptions were comparable to controls). Fetal body weight and
crown-rump length were depressed in this dose group. An increase in
short-tailed fetuses and missing vertebrae was described for the
65 mg/kg group as well as a few minor skeletal aberrations. In the
animals exposed to acrylonitrile by inhalation, these changes did not
reach statistical significance (Murray et al., 1976 and Murray et al.,
1978).
Chicken
Acrylonitrile in saline was injected into the air space or the
yolk sac of 3 day old incubated chicken eggs at concentrations of 0,
0.01, 0,1, 1 and 10 umol/egg. Embryos were examined for viability and
malformations after 14 days of incubation. Embryotoxicity was observed
in 100% and 44% in the two highest dose groups, respectively. No signs
of teratogenicity were reported (Kankaanpaa et al., 1979).
Special study on teratogeniticy of the metabolite sodium cyanide
Hamster
Pregnant hamsters were dosed with concentrations of 0.12-
0.13 mmol/kg/hr (141-153 mg/kg/day) of sodium cyanide by implantation
of osmotic minipumps from day 6-9 of gestation. Fetuses were examined
on day 11 of gestation. Maternal toxicity was noted in 4 to 7 dams
receiving 150 mg/kg/day in the form of ataxia. Five of 7 litters in
this group had 3 or more malformed fetuses whereas 2 litters were
completely resorbed. Malformations noted were exencephaly,
encephaloceles, hydropericardium, and limb and tail defects (Doherty
et al., 1981).
Special studies on the mechanism of acrylonitrile toxicity
Antidotes to cyanide poisoning were reported to protect rabbits
against the acute toxicity of acrylonitrile. The use of sodium
thiosulfate prevented the death of 3 out of 4 rabbits exposed to
75 mg/kg of acrylonitrile intravenously and delayed toxicity symptoms
and death after 100 mg/kg. Animals were dying in spite of reduced
blood cyanide levels. Similar results were obtained with rats and
guinea pigs (Hashimoto & Kanai, 1965).
In addition, these authors pretreated rabbits with L-cysteine
3 minutes before dosing with acrylonitrile. Cysteine caused a large
decrease in the levels of acrylonitrile and cyanide in the blood and
protected the animals from poisoning (Hashimoto & Kanai, 1965).
Similar results were noted with guinea pigs, rats and mice.
Groups of 10 male rats were treated with 144 mg/kg of
acrylonitrile, 15.6 mg/kg of KCN or 12.75 mg/kg of acetone cyanohydrin
(1.5 × LD50) subcutaneously. Half of the groups were pretreated with
30 mg/kg of sodium nitrite. Sodium nitrite effectively protected rats
from the lethal effects of KCN but had no effect on survival rate or
survival time of acrylonitrile (Magos, 1962).
Rats poisoned with lethal doses of acrylonitrile were protected
by cyanide antidotes only after oral administration of acrylonitrile
(150 mg/kg). After inhalation or i.p. administration of arylonitrile
cyanide antidotes were not protective. Cysteine prevented the lethal
effect of 100 mg/kg acrylonitrile i.p. even when given 2 hours after
the acrylonitrile dose (Appel et al., 1981).
A single dose of 60 mg/kg of acrylonitrile administered orally or
subcutaneously to rats caused gastrointestinal bleeding 3 hours after
treatment. This effect was enhanced after pretreatment with the
cytochrome P-450 inducing compounds phenobarbital or Aroclor 1254 and
reduced after inhibition of this enzyme with CoC12 or SKF 525A. The
authors concluded that metabolic activation of acrylonitrile is a
prerequisite for the toxic effect on the stomach (Ghanayem & Ahmed,
1983).
Special studies on mutagenicity
Bacterial
Mutagenic potential of acrylonitrile was tested in four
tryptophan-dependent Escherichia coli WP2 strains at concentrations
of 75 and 150 umol/plate, using a plate-incorporation assay. Doses
above 150 umol/plate were cytotoxic. Acrylonitrile had a weak
mutagenic effect that was not enhanced by Aroclor 1254-induced rat
liver S-9 microsomal fraction. The use of the fluctuation test
confirmed the mutagenicity of acrylonitrile in these strains at
concentrations 20-40 fold lower than the plate-incorporation test
(Venitt et al., 1977).
Acrylonitrile showed weak mutagenic activity in Salmonella
typhimurium strains TA 1535 and TA 1538 after activation with
Aroclor 1254-induced mouse liver S-9. Cells were exposed to
acrylonitrile by spotting on a lawn of bacteria, by liquid suspension
or under vapor. In the last test method, concentrations as low as
57 ppm for 4 hours caused a statistically significant increase in
revertants (Milvy & Wolff, 1977).
In a modification of the Ames test using a gradient plate of the
test compound, acrylonitrile was listed as positive in a mutagenesis
screening test with 10 strains of Salmonella typhimurium and
Escherichia coli (McMahon et al., 1979).
Aroclor 1254-induced rat liver S-9 was necessary for expression
of mutagenic activity of acrylonitrile when exposing the base-pair
substitution sensitive strains TA 1538, TA 1535, TA 1530 and TA 1950
to acrylonitrile vapor for 1 hr in a closed environment causing
concentrations of about 200 ug/plate. The frameshift-sensitive strains
TA 98 and TA 1978 and the basic-pair substitution sensitive strain
TA 100 were only weakly reverted (De Meester et al., 1978). Negative
results were found with the strains TA 1975z, TA 1532, TA 1537 and his
G 46.
Pre-treatment of Wistar rats or NMRI mice with Aroclor 1254 or
3-methyl-cholanthrene caused the liver S-9 to be more effective in
activating acrylonitrile's mutagenicity than phenobarbital- or
acrylonitrile induction. The S-9 mix prepared from mice was more
effective than that from rats. Uninduced Beagle dog liver S-9 was also
capable of activating acrylonitrile (De Meester et al., 1979).
The addition of trichloroacetonitrile, a radical scavenger,
abolished the mutagenic activity of acrylonitrile (at a concentration
of 14 umol/plate and preincubated with S-9 mixture) to Salmonella
typhimurium TA 1530 indicating a role of radical formation in the
mutagenic action of acrylonitrile (Duverger van Bogaert et al.,
1982b).
Acrylonitrile was reported to be mutagenic to Salmonella
typhimurium TA 1535 after activation by Aroclor 1254-induced hamster
liver S-9 causing 49 revertants/plate at 100 ug and 131
revertants/plate at 1000 ug per plate (Lijinski & Andrews, 1980).
Drosophila
The occurrence of sex-linked recessive lethal mutations in
Drosophila melanogaster was studied by Benes and Shram (1969)
following injection of 0.2 ul of an 0.1% acrylonitrile solution in the
abdomen of male flies. The results were inconclusive.
Mammalian
Dosages of 0, 7, 14 or 21 mg/kg body weight of acrylonitrile
(5 times per week) were given orally or intraperitoneally to groups of
6 male mice for periods of 4, 15 or 30 days. No chromosomal
aberrations were noted in the bone marrow 6 hours after the last
administration of acrylonitrile. The chemical also was found to be
negative when Sprague-Dawley rats were exposed orally to 40 mg/kg body
weight of acrylonitrile for 16 days (Rabello-Gay & Ahmed, 1980).
Male mice were injected intraperitoneally with a single dose of
20 or 30 mg/kg of acrylonitrile. Chromosome aberrations were examined
in bone marrow cells at 6, 18, 24, 48 and 72 hrs after administration,
and micronuclei in polychromatic erythrocytes at 24, 30 and 48 hrs.
Both tests yielded negative results. In addition, a dominant lethal
test was performed by mating each male with groups of 3 females
immediately after injection, and at days 7, 14, 21 and 28. The females
were sacrificed and dissected 17 days after the start of mating.
Reproductive performance of the experimental animals was comparative
to controls as were testicular weights (Leonard et al., 1981).
Syngeneic Balb/c mice were inoculated with 2-4 × 106 Balb/3T3
cells immediately prior to subcutaneous injection of acrylonitrile.
After 3-4 hr of exposure, cells were recovered for estimation of
transformation rate. Acrylonitrile was reported to have a weak
positive response (Barnett & Ward, 1979).
Primary hamster embryo cells were cultured in the presence of 0,
12, 25, 50 and 100 ug/ml of acrylonitrile. At 50 and 100 ug/ml
exposure, these celles produced foci of morphologically transformed
cells. When similar cells were pretreated with Simian adenovirus (SA7)
and subsequently treated with acrylonitrile, the viral transformation
was enhanced. When 3H-thymidine labeled hamster embryo cells were
treated with acrylonitrile, cellular DNA, subjected to alkaline
sucrose gradients, exhibited a sedimentation pattern reminiscent of
that observed for chemical carcinogens (Parent & Casto, 1979).
Acrylonitrile did not produce sister chromatid exchanges in
Chinese hamster ovary cells in culture but a significant increase was
produced when these cells were co-cultured with freshly isolated rat
hepatocytes indicating that a reactive metabolite of acrylonitrile was
transported from the hepatocytes to the CHO cells (Brat & Williams,
1982).
Concentrations of 5 × 10-4M of acrylonitrile, pretreated with
rat liver S-9 mixture, caused a significant increase in sister
chromatid exchanges as well as increased 3H-tymidine uptake in
cultured human lymphocytes (Perocco et al., 1982).
Special studies on mutagenicity of acrylonitrile metabolites
Urine (0.1 ml per plate) from mice or rats treated with a single
i.p. dose of acrylonitrile (30 mg/kg) was mutagenic in Salmonella
typhimurium TA 1530. When assayed in the presence of mouse liver S-9
mixture, this activity was decreased and pretreatment of the test
animals with phenobarbital abolished the direct mutagenicity of the
urines of acrylonitrile-treated rats and reduced that observed in the
urine of mice (Lambotte-Vandepaer et al., 1980).
The mutagenicity of rat urines was also reduced by pretreatment
of the animals with inhibitors of alcohol dehydrogenase and
mixed-function oxidases or with a radical trapping agent. The authors
postulated that a radical species or an epoxide formed in the
metabolic pathway of acrylonitrile could be the metabolites
responsible for the mutagenicity of these urines (Lambotte-Vandepaer
et al., 1981).
These same enzyme inhibitors depress the activation by rat liver
S-9 of acrylonitrile's mutagenicity with Salmonella typhimurium TA
1530 as the tester strain (Duverger-van Bogaert, 1981). Glutathione
enhanced that S-9-mediated mutagenicity of acrylonitrile suggesting a
role of GSH in the formation of mutagenic metabolites of
acrylonitrile. However, the adduct between acrylonitrile and GSH was
not mutagenic (Duverger-van Bogaert et al., 1982c),
The bile from adult male rats collected for 6 hours after an i.p.
injection of 45 mg/kg body weight of acrylonitrile, was not mutagenic
to Salmonella typhimurium TA 1538 while mutagenic metabolites from
other test compounds were excreted in the bile (Connor et al., 1979).
The known metabolite of acrylonitrile, glycidonitrile, was
reported to induce strand breaks in SV40 phage DNA in vitro, whereas
acrylonitrile did not (Peter et al., 1983b). Mutagenic activity of
this metabolite in Salmonella typhimurium tester strains TA 100 and
TA 1535 was reported by Cerna et al., (1981).
Special study on carcinogenicity
Groups of 40 male and 40 female rats were exposed to 0 or 5 mg/kg
body weight of acrylonitrile dissolved in olive oil by gastric
intubation; the control group was intubated with olive oil, 3 times
per week, for 52 weeks. All animals were kept until spontaneous death,
at which time they were necropsied and the following tissues were
examined microscopically: Zymbal gland, interscapular brown fat,
salivary glands, tongue, lungs, liver, kidneys, spleen, stomach,
intestines, urinary bladder, brain and grossly recognizable lesions.
Body weight and survival were not affected by the administration
of acrylonitrile. Although a few gliomas in the brain, mammary tumors,
forestomach papillomas and Zymbal gland carcinomas were observed, they
appeared evenly distributed among experimental animals and controls
(Maltoni et al., 1977).
In a parallel study group of 30 male and 30 female Sprague-Dawley
rats were exposed to acrylonitrile by inhalation (0.5, 10, 20 and
40 ppm). A moderate increase in mammary tumors (incidence 5/30, 10/30,
7/30, 10/30, 7/30 in females; 1/30, 0/30, 1/30, 4/30, 7/30 in males in
order of increasing dosage), Zymbal gland carcinomas, (0/30, 0/30,
1/30, 1/30, 0/30 in females; 0/30, 0/30, 1/30, 0/30, 0/30 in males),
forestomach carcinomas (0/30, 1/30, 2/30, 1/30, 0/30 in females; 0/30,
1/30, 2/30, 0/30, 3/30 in males) and brain tumors (9/30, 17/30, 11/30,
14/30, 8/30 in females; 0/30, 1/30, 10/30, 13/30, 12/30 in males)
diagnosed as gliomas was reported, but the incidences were such that
the significance of these findings is doubtful (Maltoni et al., 1977).
Other studies addressing the carcinogenic effect of acrylonitrile
are discussed under "long-term toxicity tests" and one under "special
study on reproduction".
Special study on skin and eye irritation
Acrylonitrile was mildly irritant to shaved rabbit abdominal skin
at dosages of 1,2 and 3 ml/kg applied to areas of 100, 200 and
300 cm2. The application of 0.05 ml of the compound caused mild
conjunctivitis without clouding of the cornea or papillary damage
after 1 hr (McOmie, 1949).
Special comparative studies on inhalation
Four rhesus monkeys and 2 dogs were exposed to an atmosphere
containing 56 ppm of acrylonitrile for 4 hrs per day, 5 days per week
over a 4-week period. The monkeys did not show overt signs of
toxicity, whereas 1 dog died and the other dog had intermittent
paralysis of the hind legs (Dudley et al., 1942).
From 3-16 rats, guinea pigs, rabbits and cats were exposed to
100 ppm or 153 ppm acrylonitrile, and 2 monkeys to 153 ppm for 8
weeks. At the highest exposure level, severe toxicity was noted with
many animals dying prior to completion of the study. Three female rats
at the 100 ppm level gave birth to normal pups. The dog was the most
sensitive species tested followed by monkey, cat and rabbit. Guinea
pig and rat were the least sensitive. Microscopic examination of
spleen, kidney, liver, lung, heart, pancreas, lymph nodes, stomach and
small and large intestines, showed hemosiderosis in rat spleens, renal
irritation in most animals, subacute bronchopneumonia (all species
except cat). Cats were the only species that showed signs of liver
damage (Dudley et al., 1942).
Acute toxicity
Animal Route LD50 References
(mg/kg)
mouse oral 27 Benes & Cerna, 1959
i.p. 46 Paulet & Desnos, 1961
s.c. 35 Benes & Cerna, 1959
rat oral 78 Benes & Cerna, 1959
percut. 148 NIOSH, 1979
i.p. 65-100 Knobloch et al., 1971
s.c. 80-96 Knobloch et al., 1971
Magos, 1962
guinea pig oral 50 NIOSH, 1979
percut. 202 NIOSH, 1979
s.c. 35 NIOSH, 1979
rabbit oral 93 NIOSH, 1979
percut. 250 NIOSH, 1979
i.v. 50-69 Paulet & Desnos, 1961
Hashimoto & Kanai, 1965
Short-term studies
Rat
Administration of 50 mg/kg of acrylonitrile to rats i.p.,
once/day for 3 weeks resulted in decreased body weight, leukocytosis,
increased weights of liver, kidney and heart. Organ weight changes
were confirmed microscopically as parenchymal degeneration of liver
and kidney. Damaged neuronal cells of cortex and brainstem were also
diagnosed (Knobloch et al., 1971).
Intravenous administration of 200 mg/kg of acrylonitrile to
female rats resulted in massive bilateral hemorrhagic apoplexy of
adrenal glands within 1-2 hours (Szabo et al., 1976a).
Female rats were exposed to 0, 0.05% or 0.2% of acrylonitrile in
the drinking water for 7, 21 or 60 days. Body weights, water intake
and urine output were reduced in all groups. Na+ concentration in
plasma and urine were elevated whereas K+ was only elevated in urine,
not in plasma. However, 24 hr urinary Na+ and K+ were reduced. Plasma
corticosteroids were also depressed. The adrenal zona fasciculata was
atrophic after 21 and 60 days (Szabo et al., 1976b).
Groups of 4 female rats were exposed to 0, 100 or 500 ppm of
acrylonitrile in the drinking water for 21 days. Water consumption
decreased significantly in the 500 ppm group. Food consumption was
only slightly reduced in both experimental groups. Sorbitol
dehydrogenase was elevated in the high-dose group. Relative liver
weights were comparable to controls. The livers showed no gross or
light-microscopic abnormalities (Silver et al., 1982).
Dog
Groups of 4 male and 4 female dogs were exposed for 6 months to
0, 100, 200 and 300 ppm of acrylonitrile in the drinking water.
Exposure for males was 0, 10, 16 and 17 mg/kg, for females, 0, 8,
17, 18 mg/kg respectively. The two highest doses were highly toxic
with increased mortality. Food and water consumption were decreased
at 300 ppm in both sexes and at 200 ppm in females. There were
also substantial decreases in boy weight at all dose levels.
Hematological changes in the higher dose levels were consistent with
bronchopneumonia which was chronically present. Chemical studies of
blood and urine revealed no abnormalities that were directly
associated with acrylonitrile treatment. Non-protein sulfhydryl levels
in liver and kidneys were comparable to controls in the 100 ppm group.
The higher dose levels had too few numbers surviving for meaningful
statistical analysis. Relative kidney weights were increased but these
kidneys appeared normal on histopathological examination. The 2
surviving males of the 200 ppm, and the 2 surviving females of the
300 ppm groups had a decreased relative brain weight. The lungs of
dogs at the two higher levels showed bronchopneumonia caused by
aspirated food particles. In these same groups, focal erosions and
ulcerations as well as dilation and thinning of the walls of the
esophagus were described. It was believed that acrylonitrile may have
caused irritation of the membrane of the throat (Quast et al., 1975).
Long-term studies
Rat
A combined chronic toxicity and carcinogenicity study was
performed on rats. Three groups of 100 male and 100 female weanling
rats were administered acrylonitrile in distilled water by gastric
intubation in dosages of 0, 0.1 and 10 mg/kg body weight, 7 times per
week, for 19 months and 1 week. Periodic observations were made of
appearance, mortality, growth, tissue masses and food and liquid
intake. Ophthalmoscopy was performed at pretest, 6, 12, 18 and 20
months. Comprehensive hematological examinations, clinical chemical
tests (SGPT, AP, BUN, glucose) and urinalysis were performed on 10
animals/sex/high-dose and control, routinely and low-dose as required,
at 6, 12, 18 and 20 months. All animals were necropsied.
Interim sacrifices took place at 6, 8 and 12 months on 10
animals/sex/dose. At interim and terminal sacrifices (20 months),
organ weights of brain, pituitary, adrenals, gonads, heart, kidneys
and liver were recorded for 10 animals/sex/dose. Tissue samples of 10
animals/sex/dose at each necropsy interval were subjected to
comprehensive histopathological examination.
The study was terminated at 20 months because of high mortality
in the high-dose groups (both sexes). No consistent changes suggesting
compound involvement were found in appearance, eye examinations, food
consumption, hematological, biochemical and urinary parameters. Mean
body weights of the high-dose males were consistently slightly lower
than controls. The body weights of the other groups were considered
comparable to controls throughout the study. An increase in palpable
masses of the head region was noted in high-dose males (incidence
2/100, 3/100, 12/100 for 0, 0.1 and 10 mg/kg, respectively) and
palpable masses in both head and mammary regions were reported in
high-dose females. The incidences of palpable masses in the head
region of females was 7/100, 5/10, 23/100 in order of increasing
dosage, and in the mammary region 29/100, 26/100 and 42/100. These
findings were confirmed histopathologically by an increased incidence
of astrocytomas of the brain (1/99, 2/100, 17/100 for females; 2/100,
0/97, 16/98 for males) and spinal cord, (0/100, 0/95, 1/99 for
females; 0/94, 0/93, 1/97 for males), squamous cell carcinomas and
papillomas of the Zymbal gland (ear canal) in the high-dose groups
(both sexes) and carcinomas of the mammary gland in high-dose females.
Incidences of Zymbal gland papillomas were 1/73, 0/84, 6/84 for
females; 0/80, 1/80, 8/82 for males, and Zymbal gland carcinomas 0/73,
0/84, 9/84 for females, 1/80, 0/80, 10/82 for males. The incidences of
mammary carcinomas in females were 7/101, 6/100, 22/101. In addition,
an increase was noted in adeno-carcinomas of the intestines in
high-dose males only (6/100, 1/100, 6/100) and squamous cell
carcinomas (0/99, 0/97, 18/99 in males) and papillomas (1/99, 4/99,
16/99 in females, 2/99, 6/97, 22/99 in males) in the non-glandular
stomach (anonymous, 1980a).
A second study with identical protocol was performed on rats with
the exception that acrylonitrile was administered in the drinking
water, at concentrations of 0, 1 and 100 ppm. The daily intake of
acrylonitrile was 0, 0.093 and 7.98 mg/kg for males and 0.146 and
10.69 mg/kg for females. This study was also terminated at 20 months
and the findings confirmed the results of the intubation study:
increased incidences of astrocytomas of brain (incidences: 0/99,
1/100, 32/97 in females, 2/98, 3/95, 23/97 in males) and spinal cord
(0/96, 0/99, 7/98 in females) and of squamous cell carcinomas of the
Zymbal gland (0/99, 0/95, 7/98 in females, 1/100, 0/91, 19/93 in
males) of high-dose males and females, as well as increased squamous
cell carcinomas and papillomas of the non-glandular stomach in the
high-dose groups. Incidences in stomach carcinomas were 0/100, 0/99,
0/99 in females, 0/98, 1/98, 4/97 in males and papillomas 1/100, 4/99,
7/99 in females and 3/98, 2/98, 8/97 in males. No increase in tumor
incidence in the intestines of males nor the mammary glands in females
were reported in this study, however (anonymous, 1980b).
In a third study of similar protocol, performed by the same
laboratory, rats of a different strain (100 animals/sex/dose, except
controls which consisted of 200 animals per sex) were exposed to
acrylonitrile in the drinking water at concentrations of 0, 1, 3, 10,
30 and 100 ppm for 2 years. The average daily amount of acrylonitrile
ingested for male rats was 0, 0.08, 0.25, 2.49, 8.37 mg/kg and for
female rats 0, 0.12, 0.36, 1.25, 3.65 and 10.89 mg/kg. Interim
sacrifices were performed at 6, 12 and 18 months (10 animals/sex/dose)
and the study was terminated at 23 months for females and at 26 months
for males. Early mortality was observed in both the male and female
rats exposed to 100 ppm of acrylonitrile. Tumors sites and incidence
are as follows: astrocytomas in the brain (1/99, 0/100, 1/100, 2/101,
4/95, 6/100, 23/98 in females; 0/100, 2/100, 2/100, 1/100, 2/100,
10/99, 21/99 in males in order of increasing dosage); squamous cell
carcinomas and papillomas of the Zymbal gland (ear canal), (carcinomas
0/98, 0/95, 0/94, 1/92, 2/90, 2/94, 7/86 in females, 0/95, 1/94, 0/97,
0/93, 2/88, 5/94, 8/93 in males; papillomas: 0/98, 0/95; 0/94, 1/92,
2/90, 3/94, 1/86 in females, 0/95, 1/94, 1/97, 0/93, 0/88, 2/94, 8/93
in males); squamous cell carcinomas and papillomas of the fore-stomach
in males only (combined incidence: 0/99, 0/100, 1/100, 4/97, 4/100,
4/100, 1/100) (anonymous, 1980c).
In another study acrylonitrile was administered for 2 years to
male and female rats in the drinking water at concentrations of 0, 35,
100 and 300 ppm to groups of 48 animals/sex (80/sex for control). For
the first 21 days of the study, the concentrations were 35, 85 and
210 ppm; then the two higher doses were raised to 100 and 300 ppm. The
daily intake of acrylonitrile based on water consumption was 0, 3.4,
8.5 and 21.2 mg/kg for males and 0, 4.4, 10.8 and 25.0 mg/kg for
females. Periodic observations of appearance, body weights, food and
wate consumption, condition of the teeth and palpable masses were
reported. At predetermined intervals, blood and urine were collected
from 10 rats/sex of control and high dose of hematological and
biochemical measurements and urinalysis. Necropsy and gross pathology
were performed on all animals that were not lost through autolysis. On
death or at termination at 24 months, microscopic examination was
performed on a complete set of tissues from the control and high-dose
animals and on 23 selected organs or tissues with obvious lesions,
from the other exposure groups (Quast et al., 1980a).
After 9 months of treatment, the animals of the highest dose
groups showed signs of toxicity as indicated by an unthrifty
appearance. There was a dose-related decrease in food consumption
(except in male rats at the lowest dose level), and a concomitant
dose-related decrease in water consumption. Early mortality was
observed at the high dose level in males and at all dose levels in
females. The reduced water intake was reflected in an increased
urinary specific gravity in the 300 ppm groups and the 100 ppm female
group. There were decreases reported in white blood cell count, packed
cell volume and hemoglobin and increases in blood urea nitrogen in the
300 ppm groups at some of the test points. Increased incidences of
astrocytomas in the brain (incidence 1/80, 17/48, 22/48, 24/48 in
females, 1/80, 8/47, 19/48, 23/48 in males), were reported for all
dose groups in a dose-related fashion, occurring predominantly in the
cerebral cortex and the brainstem. Possible pre-neoplastic foci of
glial cells were also noted. Tumors in the ear canal (Zumbal gland)
were progressively growing ulcerated tumors, causing displacement of
the lower jaw and consequent interference with food consumption in
some animals. These tumors were observed at increased incidence and
severity in the 300 ppm group for both sexes, and all dose groups for
the females(1/80, 5/48, 8/48, 18/48 in females, 3/80, 4/47, 3/48,
16/48 in males). Both papillomas and carcinomas were found in the
non-glandular portion of the stomach at 100 and 300 ppm, with a
progression from hyperplasia and hyperkeratosis, to papilloma and,
finally, to carcinoma being apparent (combined tumor incidence 1/80,
1/48, 12/48, 30/48 in females and 0/80, 2/47, 23/48, 39/48 in males).
Squamous cell papillomas and carcinomas of the tongue were increased
in the high-dose groups of both sexes (0/80, 1/48, 2/48, 12/48 in
females, 1/80, 2/47, 4/48, 5/48 in males), and carcinomas of the small
intestine were increased in the 100 and 300 ppm female groups (0/80,
1/48, 4/48, 4/48). Mammary gland tumors in females (58/80, 42/48,
42/48, 35/48) were common and were one of the major reasons for animal
deaths prior to the end of the study. An apparent decrease in this
tumor type in the 300 ppm group could probably be attributed to the
early death of animals at this dose level. The early mortality could
also be implicated in the reduced incidences of pituitary, thyroid,
adrenal, pancreas and uterus tumors (Quast et al., 1980a).
A study in which groups of 100 male and 100 female rats were
exposed to vapor levels of 0, 20 and 80 ppm of acrylonitrile for 2
years for 6 hours per day, 5 days per week, essentially confirmed the
occurrence of tumors in the brain (0/100, 4/100, 16/100 in females,
1/100, 4/99, 15/99 in males) and ear canal (Zymbal gland) (0/100,
0/100, 10/100 in females, 1/100, 3/100, 11/100 in males) in both sexes
as well as epithelial tumors of the tongue (1/96, 0/14, 7/89 in males)
carcinoma of the small intestines in males (2/99, 2/20, 14/98) and
mammary adenocarcinomas in females (9/100, 7/100, 20/100). General
toxic effects were also observed in this study in the form of
unthrifty appearance, decreased body weight gain, early mortality,
increased palpable masses in the ear region (male and female) and in
the mammary region (female only) as well as signs of irritation of the
respiratory tissues. No consistent compound-related changes were noted
in hematological, biochemical parameters and urinalyses (Quast et al.,
1980b).
OBSERVATIONS IN MAN
Acute intoxication
Non-fatal intoxication by acrylonitrile was reported in workers
who cleaned polymerizers in rubber-manufacturing plants. Exposure
was estimated at 16-100 ppm for 20 to 45 minutes. All workers
complained to nasal irritation and an oppressive feeling in the upper
respiratory passages. Dull headaches, nausea, apprehension and nervous
irritability were frequent complaints. In more severe cases anemia and
jaundice were diagnosed (Wilson, 1944; Wilson et al., 1948).
Similar symptoms of headache, vertigo, nausea and vomiting were
reported by a chemist distilling acrylonitrile (Sartorelli, 1966),
including tremors, uncoordinated movements and convulsions. Baxter
(1979) has summarized the sequence of symptoms of acrylonitrile
poisoning in man as follows: irritation of eyes and nose, limb
weakness, labored breathing, dizziness, impaired judgement, cyanosis
and nausea, collapse, irregular breathing, convulsions.
Case reports have been presented of lethal intoxications of
patients after exposure to fumigant mixtures containing acrylonitrile
(Davis et al., 1973; Radimer et al., 1974). The latter report
implicated acrylonitrile as the causative agent for severe epidermal
necrosis resembling burn blisters.
Epidemiological studies
A retrospective cohort study of 1345 employees with potential
exposure to acrylonitrile analysing cancer incidence and mortality
from 1956-1976, reported the occurrence of 25 cases of cancer with
20.5 expected. Of these, 8 were respiratory cancer with 4.7 expected.
A trend toward increased risks was seen with increased duration and
severity of exposure. Twenty cancer deaths were found with 17.4
expected (O'Berg, 1980).
The mortality experience of workers exposed to acrylonitrile at
two plants in Texas and Alabama was studied with special emphasis on
overall cancer rate, cancer of the lung and colon. Total cohorts for
this study was 352. The follow-up period was around 15 years. There
were no statistically significant differences between observed and
expected numbers of death for any of the cause-of-death category
examined (Zack, 1980).
Comment: Considering the small size of the study cohort and the
relatively short period of follow-up, this study is probably too
insensitive to detect increased cancer risk.
In an analysis of mortality among 327 employees of a rubber
chemicals plant who had potential exposure to acrylonitrile, 9 deaths
from lung cancer were found versus 5.9 expected based on U.S.
mortality rates of white males or 4.7 expected based on mortality
rates of other rubber workers in the same area. The excess was
greatest among men who worked 5 or more years and who died 15 years
after starting work in the plant (Delzell & Monson, 1982).
A cohort of 1111 men working with acrylonitrile or acrylic fibers
in the UK was analysed for mortality and cancer rates. Exposure
occurred between 1950-1968 with a follow-up period until 1978. In the
group of men exposed to acrylonitrile for at least one year, the total
number of deaths was smaller than expected. An excess of deaths from
all cancers was found, arising mainly from cancers of the lung,
stomach, colon and brain, but the excess was not statistically
significant (Werner & Carter, 1981).
Analysis of chromosomes in lymphocyte cultures of 18 workers who
had been exposed to vapors containing acrylonitrile for an average of
15.4 years did not show an increase in abnormalities over an
age-matched control group of non-exposed workers (Thiess & Fleig,
1978).
Comments
Orally administered acrylonitrile is rapidly absorbed. The
absorbed material is distributed throughout the body with highest
concentrations occurring in blood, liver, kidney, lung of adrenal
cortex and stomach. Pharmacokinetic studies indicate of two
compartment model for elimination, with half-life ranging from 3-5 hr,
and 55-70 hr. Excretion of the metabolic products is mainly in the
urine. The metabolism involves cytochrome P-450 dependent mixed
function oxidase systems, followed by glutathione conjugation. The
urinary metabolites identified include thiocyanate,
N-acetyl-S(2-cyanoethyl) cysteine and 4-acetyl-3-carboxy-5-cyanotetra-
hydro-1,4-2H-thiazine. The major biliary metabolites are glutathione
conjugates of acrylonitrile.
Acrylonitrile was teratogenic to hamsters and rats.
Acrylonitrile was weakly mutagenic in a number of Salmonella
typhimurium strains after activation with S-9 mixtures. Urine from
rats and mice treated with a single i.p. injection of acrylonitrile
was also shown to have mutagenic activity in the Ames test
(strain TA 1530).
Acrylonitrile, when administered to rats by gastric intubation,
or in the drinking water, resulted in statistically significant
increases of tumor incidence at multiple sites, including:
astrocytomas in brain and spinal cord, squamous cell carcinomas of the
Zymbal gland (ear canal gland), carcinomas and papillomas of the
non-glandular stomach. These findings were confirmed in other 2-year
drinking water and inhalation studies in rats. Inhalation study showed
increased incidences of tumors of the brain and Zymbal gland, and in
one study tumors of the tongue.
The suspicion of carcinogenicity of acrylonitrile has been
supported by a number of epidemiological studies of factory workers
exposed to acrylonitrile vapors. There is a slight indication of
increased lung, stomach, colon and brain tumors.
EVALUATION
Level causing no toxicological effect
Acrylonitrile is considered to be teratogenic in hamsters and
rats, and carcinogenic in rats when administered orally and when
inhaled. A "no effect" level in experimental animals has not been
established.
Provisional acceptance
Human exposure to acrylonitrile in food as a result of its
migration from food contact material should be reduced to the lowest
levels which are technologically achievable.
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